Abstract
BackgroundAromatic L-amino acid decarboxylase (AADC) enzymes catalyze the synthesis of biogenic amines, including the neurotransmitters serotonin and dopamine, throughout the animal kingdom. These neurotransmitters typically perform important functions in both the nervous system and other tissues, as illustrated by the debilitating conditions that arise from their deficiency. Studying the regulation and evolution of AADC genes is therefore desirable to further our understanding of how nervous systems function and evolve.ResultsIn the nematode C. elegans, the bas-1 gene is required for both serotonin and dopamine synthesis, and maps genetically near two AADC-homologous sequences. We show by transformation rescue and sequencing of mutant alleles that bas-1 encodes an AADC enzyme. Expression of a reporter construct in transgenics suggests that the bas-1 gene is expressed, as expected, in identified serotonergic and dopaminergic neurons. The bas-1 gene is one of six AADC-like sequences in the C. elegans genome, including a duplicate that is immediately downstream of the bas-1 gene. Some of the six AADC genes are quite similar to known serotonin- and dopamine-synthetic AADC's from other organisms whereas others are divergent, suggesting previously unidentified functions. In comparing the AADC genes of C. elegans with those of the congeneric C. briggsae, we find only four orthologous AADC genes in C. briggsae. Two C. elegans AADC genes – those most similar to bas-1 – are missing from C. briggsae. Phylogenetic analysis indicates that one or both of these bas-1-like genes were present in the common ancestor of C. elegans and C. briggsae, and were retained in the C. elegans line, but lost in the C. briggsae line. Further analysis of the two bas-1-like genes in C. elegans suggests that they are unlikely to encode functional enzymes, and may be expressed pseudogenes.ConclusionsThe bas-1 gene of C. elegans encodes a serotonin- and dopamine-synthetic AADC enzyme. Two C. elegans AADC-homologous genes that are closely related to bas-1 are missing from the congeneric C. briggsae; one or more these genes was present in the common ancestor of C. elegans and C. briggsae. Despite their persistence in C. elegans, evidence suggests the bas-1-like genes do not encode functional AADC proteins. The presence of the genes in C. elegans raises questions about how many 'predicted genes' in sequenced genomes are functional, and how duplicate genes are retained or lost during evolution. This is another example of unexpected retention of duplicate genes in eukaryotic genomes.
Highlights
Aromatic L-amino acid decarboxylase (AADC) enzymes catalyze the synthesis of biogenic amines, including the neurotransmitters serotonin and dopamine, throughout the animal kingdom
Rescue of the bas-1 mutant with an AADC-homologous sequence The bas-1 gene maps to chromosome III, between dpy-17 and unc-32. When this region was sequenced by the C. elegans Genome Sequencing Consortium, two AADChomologous predicted genes, designated C05D2.4 and C05D2.3, were found to be located close together on a single cosmid, C05D2 (Fig. 2A)
To confirm further that C05D2.4 is the bas-1 gene, we identified the mutations in four bas-1 mutant alleles; we examined the phenotypes of deletion mutants in C05D2.4 and C05D2.3 generated by the C. elegans Gene Knockout Consortium (GKC)
Summary
Aromatic L-amino acid decarboxylase (AADC) enzymes catalyze the synthesis of biogenic amines, including the neurotransmitters serotonin and dopamine, throughout the animal kingdom. These neurotransmitters typically perform important functions in both the nervous system and other tissues, as illustrated by the debilitating conditions that arise from their deficiency. Aromatic L-amino acid decarboxylase (E.C. 4.1.1.28, AADC) catalyzes the second enzymatic step in synthesis of the neurotransmitters dopamine and serotonin, which are found in neurons of all animals (Figure 1). Other subgroup II enzymes include histidine, tyrosine, tryptophan and glutamate decarboxylases [5]; in animals some of these enzymes mediate synthesis of other biogenic amines (e.g., histamine, tyramine, octopamine) and GABA. Different genes encode PLP-dependent decarboxylase enzymes for histamine, octopamine and GABA synthesis
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